The objective of the proposed research is the solution of the problem of the metabolic balance of chlorpromazine (CPZ). Less than 50% of the adminstered dose has been accounted for in urine and less than 5% in feces in man and in rhesus monkeys. It is therefore proposed to carry out a balance study. 1. Radiolabeled CPZ will be used to locate (in rats) the material excreted and the amounts present in individual tissues. 2. Repetition (in the same species) using deuteriated drug, and examination of the tissues (using the distribution data from 1) will then be undertaken. 3. HPLC will be used to separate the components in 1 (to establish number, retention time, and size of peaks obtained), and in 2 (to collect, identify by GC-MS and quantitate by inverse stable isotope dilution measurements using the nondeuteriated compounds as internal standards). 4. An efficient extraction protocol has been developed for blood (plasma and/or cells) and analytical methods have been devised using GC-MS inverse stable-isotope dilution measurements for identification and quantitation of drug and metabolites. 5. These procedures will be applied to a clinical study on human patients to correlate clinical efficacy with blood levels and pathway of drug metabolism. 6. In particular, correlation between clinical response and blood level of drug and the major pharmacologically effective metabolite (7-OH-CPZ) will be monitored and the pharmacokinetics and mechanisms of formation of 7-OH-CPZ from CPZ investigated.